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Chemotherapy Chemotherapy Subcommittee: George Brenner (Chair) [email protected] Gudas, Lorraine J. [email protected] Lazo, John S, [email protected] Matta, Jaime [email protected] Greg Reed <[email protected]> Vrana, Kent, [email protected] Basic Principles Of Antimicrobial Therapy Recommended Curriculum Equivalent: 1 hr Learning Objectives Define the terms: antibiotics, selective toxicity, therapeutic index, bacteriostatic and bactericidal, chemotherapeutic spectrum. Understand the MIC and MBC values. Describe the terms synergism and antagonism. Discuss the classification of antimicrobial drugs based upon the mechanism of action. Explain the modes of action of various antimicrobial drugs. Define bacterial resistance and illustrate the mechanisms involved in acquiring bacterial resistance. Describe the basic principles of combination therapy with antimicrobial drugs. Cell Wall Synthesis Inhibitors Recommended Curriculum Equivalent: 2 hr Drug Classes and Drugs to consider Penicillins Cephalosporins and vancomycin AMPICILLIN CEFTRIAXONE AZTREONAM CEPHALEXIN PENICILLIN G VANCOMYCIN PIPERACILLIN cefaclor IMIPENEM cefazolin amoxicillin cefepime clavulanic acid cefotaxime cloxacillin cefoxitin indanyl carbenicillin ceftazidime meropenem cefuroxime methicillin fosfomycin mezlocillin nafcillin oxacillin penicillin V sulbactam tazobactam. ticarcillin Learning Objectives Mechanism of action Describe the structural relationship of the penicillin molecule with antimicrobial activity. Explain the mechanism of action of β-lactam antibiotics Understand the principle of combination of inhibitors of β-lactamase with penicillins (List such combinations). Explain the pharmacological basis for combining imipenem with cilastatin. Describe the structural differences between penicillins and cephalosporins. Explain the mechanism of action of cephalosporins. Discuss the mechanism of action of vancomycin and of fosfomycin. Pharmacokinetics Describe the pharmacokinetic properties of penicillins. Describe the repository penicillins. List the penicillinase-resistant penicillins. Describe the four generations of cephalosporins with specific examples and the differences in their antimicrobial spectrum and pharmacokinetic properties. Describe the pharmacokinetic properties of vancomycin. Adverse effects and contraindications Describe the principal adverse effects of penicillins. Describe the principal contraindication of penicillins. Describe the adverse effects due to cephalosporins and vancomycin. Explain the terms superinfection and cross-hypersensitivity. Therapeutic uses Discuss primary therapeutic indications for penicillin G. Describe the indications for broad-spectrum penicillins. Describe the antimicrobial activity of monobactams and carbapenems. Describe the main therapeutic indications of cephalosporins and vancomycin. Clinical Pharmacology Vancomycin use should be reserved for treatment of MRSA infections. Carbapenems and 3rd and 4th generation cephalosporin antibiotics should be reserved for patients with very serious polymicrobial infections. Carbapenems can reduce the serum concentration of valproate, leading to recurrence of seizures. Relevance USMLE topic Principles of therapeutics Cardiovascular System – Abnormal Antimicrobials and antiparasitics processes AAMC Medical School Objectives Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 and diseases Protein Synthesis Inhibitors Recommended Curriculum Equivalent: 1 hr Drug Classes and Drugs to consider Aminoglycosides Macrolides Streptogramins GENTAMICIN AZITHROMYCIN quinupristin/dalfopristin amikacin CLARITHROMYCIN neomycin ERYTHROMYCIN streptomycin telithromycin tobramycin Lincosamides Oxazolidinones Tetracyclines clindamycin LINEZOLID DOXYCYCLINE TIGECYCLINE minocycline tetracycline Others MUPIROCIN Chloramphenicol Learning Objectives Mechanism of action Discuss the mechanism of action of each class of protein synthesis inhibitors. Explain the mechanism of acquired drug resistance to aminoglycosides, tetracyclines, and macrolides. Explain the rational basis for combination therapy with an aminoglycoside and a penicillin, cephalosporin, or vancomycin. Pharmacokinetics Describe the pharmacokinetic properties of each class of protein synthesis inhibitors, including their routes of administration. Explain the importance of peak and trough levels of aminoglycosides. Discuss the need of and the method of dose adjustment for aminoglycosides in patients with compromised renal function. Adverse effects and drug interactions Discuss the main toxicities of each class of protein synthesis inhibitors. Describe the major drug interactions of macrolides due to inhibition of cytochrome P450 enzymes. Therapeutic uses Describe the primary therapeutic indications for each class of protein synthesis inhibitors. Discuss the therapeutic options for treating skin and soft tissue infections, and systemic infections due to methicillin-resistant or vancomycin-resistant bacteria. Clinical Pharmacology Use of macrolide antibiotics in patients receiving cacium channel blockers is associated with an increased risk of hypotension due to inhibition of CYP3A4 activity. Macrolide antibiotics also increase the risk of toxicity to statins metabolized by CYP3A4. Use of linezolid for more than 10 days is associated with bone marrow depression. Relevance USMLE topic Principles of therapeutics Cardiovascular System – Abnormal Antimicrobials and antiparasitics processes AAMC Medical School Objectives Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 and diseases Inhibitors of Nucleic Acid metabolism and Drugs interfering with intermediary metabolism Recommended Curriculum Equivalent: 1 hr Drug Classes and Drugs to consider Fluoroquinolones Rifamycins CIPROFLOXACIN RIFAMPIN levofloxacin rifaximin Nitroimidazole Dihydrofolate reductase inhibitors METRONIDAZOLE COTRIMOXAZOLE trimethoprim Sulfonamides Other Agents COTRIMOXAZOLE DAPTOMYCIN sulfamethoxazole FIDAXOMICIN nitrofurantoin Learning Objectives Mechanism of action Explain the mechanism of action of each class of antibiotics. Discuss the synergistic inhibition due to sequential blockade with cotrimoxazole. Learn the adverse effects of ciprofloxacin, including contraindications in children and pregnant women. Pharmacokinetics Describe the pharmacokinetics properties of each class of antibiotics. Describe the drug interactions of fluoroquinolones, including the effect of ingested cations on drug absorption. Adverse effects Describe the major toxicities of each class of drugs. Therapeutic uses Describe the therapeutic indications each class of antimicrobial drugs. List the advantages of newer fluoroquinolones over ciprofloxacin. Describe the major therapeutic indications of sulfonamides alone, and in combination with trimethoprim (cotrimoxazole). Discuss the emergence of microbial resistance to cotrimoxazole and fluoroquinolone drugs, and its implications for the treatment of urinary tract infections and gonorrhea. Describe the role and use of various drugs in the treatment of methicillin-resistant Staphylococcus aureus infections. Describe and compare the role of metronidazole, vancomycin, and fidaxomicin in the treatment of Clostridium difficile infections. Discuss the therapeutic options for treating traveler’s diarrhea. Clinical Pharmacology When administered concurrently with warfarin, metronidazole is associated with an increased anticoagulant activity. Caution in using rifampin with other drugs metabolized by CYP3A4 due to its enzyme induction property. Relevance USMLE topic Principles of therapeutics Cardiovascular System – Abnormal Antimicrobials and antiparasitics processes AAMC Medical School Objectives Topic C Project Report X Patient Safety Drug treatment of common conditions Table 1 and diseases Antimycobacterial Drugs Recommended Curriculum Equivalent: 1 hr Drugs to consider ETHAMBUTOL azithromycin ISONIAZID clarithromycin RIFAMPIN clofazimine PYRAZINAMIDE dapsone RIFAPENTINE rifabutin streptomycin thalidomide Learning Objectives Mechanism of action List the first line antitubercular drugs and explain their mechanisms of action. Define the various phases of actively and slow growing Mycobacterium tuberculosis and compare the relative effectiveness of various drugs. Describe the drugs used in the treatment of Hansen's disease and their mechanism of action. Pharmacokinetics Describe the pharmacokinetic profile of isoniazid and rifampin. Adverse effects and drug interactions Describe the adverse effects of isoniazid, rifampin, ethambutol and pyrazinamide. Explain the drug interactions of rifampin with anticoagulants and other drugs, such as oral contraceptives. Therapeutic uses Describe the regimen recommended for treatment of latent tuberculosis (formerly prophylaxis) and active tuberculosis. Explain the rationale for newer short-course regimens for latent and active tuberculosis, including the use of isoniazid and rifapentine. Describe the emergence of multidrug-resistant tuberculosis and its implications for the treatment of these infections. Discuss the use of rifabutin, clarithromycin and azithromycin for treatment of Mycobacterium avium complex. Describe the drugs used for reversing the lepra reactions and the erythema nodosum leprosum reaction. Explain the WHO regimen for treatment of leprosy. Clinical Pharmacology Mostly covered already in other sections of this document. Nothing special to add here. Relevance USMLE topic Principles of therapeutics Cardiovascular System – Abnormal
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